The broad, long-term objective of this proposal is the synthesis and development of a new series of radloimmunoconjugates as therapeutic radiopharmaceuticals for cancer radiation therapy based on metal complexes of macrocyclic N-heterocyclic carbenes. The first objective of this proposal is the synthesis of a new series of macrocycles, termed carbeneporphyrinods, in which one or more pyrrole units in a porphyrinoid ring or expanded porphyrinoid ring have been replaced with N-heterocyclic carbenes. Several examples have already been synthesized in the Youngs' research group. The second objective of this proposal is the synthesis of metal complexes of the carbeneporphyrinoids. The carbeneporphyrinoids and their expanded analogs will have novel chelating properties and cavity sizes and would bind to a variety of metals. The stability of the metal complexes used as therapeutic radiopharmaceuticals is extremely important. N-heterocyclic carbenes bind very strongly to transition and main group metals and current data indicate that carbeneporphyrinoids will bind more strongly to metal centers than do other macrocycles used in radiopharmaceuticals. The metals to be focused on in this project in the long term will be those that have or potentially have importance in radiation therapy as Beta particle emitting radionuclides. The first metal to be explored in this regard will be 111 Ag. The third objective of this proposal is to study the in vitro and in vivo stability of these new complexes. The silver carbeneporphyrinoids are extremely stable. The fourth objective of this proposal is to bind, by a linker group, the in vivo stable metallocarbeneporphyrinoids to targeting molecules that selectively target cancerous tumor cells producing a vehicle, chelator, metal species that will be called an immunoconjugate. Two types of targeting groups, nitroimidazoles and biotin, will be used. The fifth objective of this proposal will be to assess the impact and targeting ability of the metallocarbeneporphyrinoid complexes and their radioimmunoconjugates on cells. The sixth objective of this proposal will be to determine toxicity, clearance, and the effectiveness of the targeted metallocarbeneporphyrinoid in reducing carcinoma in small animals.